Menopause Induces Oxidative Stress
[Pages:28]Menopause Induces Oxidative Stress
Claudia Camelia Calzada Mendoza and Carlos Alberto Jim?nez Zamarripa
Additional information is available at the end of the chapter
Chapter 12
1. Introduction
1.1. Menopause: endocrinology and symptoms
Menopause is a physiologic process in women that occurs around 45-55 years old, which is defined as permanent cessation of menstruation by one year in row [1]. The age of meno- pause depends on multiple factors such as number of ovules from the female at birth, the frequency of loss of these ovules through her life and the number of ovarian follicles re- quired maintaining the menstrual cycle. The diagnosis of menopause is retrospective and is established after a year without menses [2], and their symptoms may have different intensi- ty for each woman [3].
This process is characterized by gradual decrease of estrogen (E) secretion and changes re- lated with sex hormones, so that estradiol levels ranging from 5 to 25 pg/mL, while increas- ing titers of gonadotrophins, so that the values of follicle stimulating hormone (FSH) between 40 and 250 mU/mL and luteinizing hormone (LH), from 30 to 150 mU/Ml [4, 5].
Irregular uterine bleeding is a characteristic symptom which is due to both depletion and resistance of ovarian receptors to gonadotropins and increased FSH, leading to alterations in the volume and frequency of bleeding (polymenorrhea, hypo-or menorrhagia, oligomenor- rhea) [6, 7].
Among symptoms are those related to the genitourinary tract by the common embryological origin of vulva, vagina, bladder, and urethra, consequently alterations as dysuria, urinary urgency and incontinence, epithelial atrophy, decreased production of mucus and vaginal dryness (phenomena that can cause dyspareunia), urethritis, vaginitis or cystitis and local infections [8, 9, 10] (Figure 1).
? 2013 Mendoza and Zamarripa; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
290 Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants
Figure 1. Main genitourinary abnormalities according to age in women [10].
Figure 2. Changes observed in muscle mass and strength after menopause [16].
Hot flushes are one of the main symptoms associated with menopause and occur in more than 75% of menopausal, consisting of intense episodes of heat that begins on chest and spreads to face, sweating, and flushing of face. Hot flushes are associated with headache,
Menopause Induces Oxidative Stress 291
anxiety and palpitations, and it usually lasts 2-4 minutes and can vary in frequency, in some women may be daily while others may have one episode per month [11, 12]. The mechanism of hot flushes is not clear, however, it is known that hypothalamus, pituitary gonadotropin releasing hormone and gonadotrophins may be involved in hot flushes [13]. Another fre- quent symptom is an oral dryness and intense burning sensation that affects mainly the tongue and sometimes lips and gums [14]. On the other hand decreases the content of collagen and elastic fibers of the skin, so that it becomes thinner and brittle losing elasticity and firmness. The epidermis thins, increases water loss and reduces the number of blood vessels, compromising the supply of oxygen and nutrients [15]. Additionally aging is associated with a natural decline in physiological functions, including a loss of muscle mass and strength. Overall, the decline in muscle mass averages 0.4 to 0.8 kg per decade, starting at the age of 20 years, especially around meno- pause [16] (Figure 2). Another alteration that occurs is the osteoporosis, which is defined as a skeletal disorder characterized by decreased bone density and an increased risk of fractures [17, 18]. Before reports have confirmed that postmenopausal women have highest incidence of hip fractures [19, 20, 21] (Figure 3).
Figure 3. Bone mineral density values by age in women. Bone mineral density decreases around menopause [21].
Menopause is a stage that favors weight gain and development or worsening of obesity, and causes of this problem are many; some are clearly related to hypoestrogenism and oth- er age-dependent, conditioning increased intake and decreased energy expenditure [22, 23] (Figure 4). During this period there is an abnormal atherogenic lipid profile characterized by increased lipoprotein cholesterol, low density (LDL-C), triglycerides (TG) and small dense LDL parti- cles [24] with reduced HDL-C and elevated serum glucose and insulin, perhaps as a direct result of ovarian failure or indirectly as a result of central redistribution of body fat, and this favors the formation of atheromatous plaques and progression of coronary atherosclerosis
292 Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants
and therefore cardiovascular disease incidence increases substantially in postmenopausal women [25, 26]. Other disorders such as obesity and metabolic syndrome also occurs at menopause, suggesting that menopause may be the trigger of the metabolic syndrome at that stage of life [27, 28].
Figure 4. Body fat distribution. Android-type distribution is present in postmenopausal women. DXA= Dual-energy Xray absorptiometry [23].
Postmenopausal women have higher insulin resistance than premenopausal, which could participate to age, the increase in total body fat, central adiposity, estrogen deficiency, alter- ations in lipid profile and glucose homeostasis and insulin are more frequent and favor the high cardiovascular morbidity and mortality after menopause. In this sense the transition of menopause is marked by changes in hormonal balance, with increased visceral fat, which are associated with insulin resistance, although it has been found that the change in insulin sensitivity does not alter the lipid profile in early postmenopausal women [24, 26] (Figure 5).
Figure 5. Changes lipid during transition from premenopause to Postmenopause [24].
Menopause Induces Oxidative Stress 293
Depression occurs frequently in postmenopausal women, which is explained by the loss of estrogenic effect in modulating neuronal excitability, synaptic plasticity, neuronal survival induced expression of regenerative responses, regional neurogenesis, regulation of differen- tiation and neuronal development [29], in the processes of cognition, modulation of mood and other mental states, as well as improving learning and memory [30], regulate the syn- thesis of tryptophan hydroxylase which is the limiting enzyme in serotonin synthesis so this decline in estrogen at menopause may explain the occurrence of psychological symptoms characteristic of depression (fatigue, irritability, sleep problems, abrupt changes of mood, [31]. With respect depressive symptoms in the Multiethnic Study of Atherosclerosis were analyzed testosterone, estradiol, steroid hormone binding globulin (SHBG) and dehydroe- piandrosterone; indicating that in early postmenopausal women, sex hormones were associ- ated with incident depressive symptoms [32].
2. Pro and antioxidants propierties of estrogens
Throughout menopause there are factors that predispose women to the development of oxi- dative stress, such as estrogen deficiency, as it has been confirmed that they have an antioxi- dant capacity independently of its binding to receptors, so for example the 17-estradiol (E2), estriol, estrone, ethinylestradiol and 2-hidroxiestradiol besides reducing neuronal death with antioxidant activity, due to the presence of an intact hydroxyl group on ring A of the molecule [33].
Estrogens are synthesized from different androgen precursors such as androstenedione and testosterone, yielding as products estrone and 17-estradiol, respectively. The synthesis is catalyzed by aromatase (ARO), the enzyme cytochrome P450 (CYP19) and estrogen synthe- sizing different tissue-specific manner, and the major estrogen in adipose tissue is estrone, the placenta is estriol and in cells granulosa is 17-estradiol [34].
The 2-hidroxiestradiol and 2-hydroxyestrone (4-hidroxiestradiol type) (Figure 6) can partici- pate in redox cycling to generate free radicals such as superoxide and chemically reactive es- trogen semiquinone/quinone, which can damage DNA and other intracellular constituents.
4-hidroxiestradiol participates in a redox cycle to generate free radicals such as superoxide, and intermediate semiquinone/quinone, these intermediaries may induce cell transforma- tion and initiate tumoral growth [35].
4 - hydroxyestrogens have estrogenic effects and can stimulate the growth of cell lines of breast cancer, with greater intensity than the 4-hydroxyestrone are unstable and can become highly reactive quinone with the formation of semiquinones as intermediary, this reaction produces oxygen free radicals, which can have toxic effects on DNA, such effects include the formation of 8-hydroxy-2-deoxiguanosine a mutagen, resulting from oxidative damage. The toxic effect of 4-hydroxyestrogens probably is prevented under normal conditions intracel- lular defense mechanisms. Oxygen free radicals can be removed immediately transformed into water by enzymes such as catalase and superoxide dismutase and antioxidant vitamins
294 Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants
such as ascorbic acid and alpha tocopherol, quinone themselves can be inactivated by sulfo compounds, such as glutathione [36].
Figure 6. Estrogen metabolism.
Menopause seems to accelerate the development of atherosclerosis and cardiovascular dis- eases and in order to identify this correlation, was assessed the correlations between intimamedia thickness, homocysteine serum levels and oxidative stress both in fertile and postmenopausal women and it was founded that were increased levels of homocysteine, ox- idative stress and intima-media tickness (IMT) in postmenopausal women having a positive correlation with IMT, which reinforce the idea that a hyperhomocysteinemia may play a role in the progression of atherosclerosisas a result the lack of estrogens [37]. Vasculo protective effects of estrogen are due in part to the modulation of the balance be- tween nitric oxide (mainly derived from endothelial vasodilator molecule) [38] and superox- ide anion (oxygen-free radical highly reactive), promoting the availability of the first such so the lack of protection induces high levels of oxidative stress and low concentrations of NO, these processes are interacting with hypertension, as seen in menopause. In addition, estro- gen induces the expression of oxide reductasesthiol / disulfide, such as disulfide isomerase, thioredoxin, thioredoxinreductase and glutaredoxin in the endothelium and inhibits apopto- sis mediated by hydrogen peroxide. On the other hand has been described that genetic fac- tors related to dyslipidemia are most important than due to age, for example antioxidant enzymes (SOD, catalase, GR, inflammatory markers CPR, ALT), oxidative stress (O(2)(-), LOO?), hypoxia (HBNO) and all this related to increase vascular resistance, disorders in oxygen supply in tissue and hypoxic competitions of there metabolism may cause, postme- nopausal hypertension, hart ischemic disease, impaired hepatic beta-oxidation of fatty acids and hepathosteatosis [39].
Menopause Induces Oxidative Stress 295
17--estradiol plays a critical role in neuroprotection through both genomic and non-genom- ic mechanisms and recently was discovered that a new G-protein-coupled receptor 30 (GPR30) participates in the neuroprotection against oxidative insult, which is agonist G1. E2 attenuated apoptosis induced by H2O2 exposure, furthermore, G1 or E2 significantly in- creased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Bcl-2 and pro-caspase-3, which is an anti-apoptotic effect [40].
3. Oxidative stress and postmenopause
Actually several oxidative stress biomarkers have been studied in menopause, however, each researcher has used different marker, methodologies and women with dissimilar char- acteristics (age, ethnic group, postmenopause time), fact does difficult to make a conclusion about the development of oxidative stress during peri, menopause and postmenopause.
Recently has been propose as indicator to -glutamyltransferase (GGT) which is an enzyme involved in the transfer of the -glutamyl residue from -glutamyl peptides to amino acids, H2O, and other small peptides and can be donated by glutathione [41]. On the other hand, GGT is also involved in the production of glutathione [42], which is limited by cysteine availability. GGT participates in the pathway of extracellular GSH in consequence the bio- synthesis of cellular glutathione, the most important cell antioxidant, depends of GGT activ- ity; hence this enzyme may play an important role in the anti-oxidative defense system of the cell [43].
Abdul et al, founded a highly significant reduction in glutathione levels in the post-menopaus- al-group which could be due to the increase in its free radical scavenging property and in- creased consumption to counteract the oxidative stress and to inhibit membrane lipid peroxidation which indicates that the increase in serum GGT with enhanced oxidative stress and reduced antioxidant defense system in the post-menopausal women may lead to the spec- ulation that GGT could be considered an index or a oxidative stress marker [43] (Table 1).
Serum level
GGT (U/L) GSH (mmole/L) MDA (?mole/L)
Premenopausal Group (n=17)
5.96?2.99 0.62?0.17 1.04?0.06
Postmenopausal Group (n=16) 9.44?2.89 0.47?0.11 1.32?0.05
p value
0.025 0.008 0.035
Table 1. Serum -glutamyltransferase, glutathione and malondialdehyde levels in the pre- and postmenopausal women [43].
Supplementary it was found that perimenopausal women have higher total cholesterol val- ues and lower paraoxonase-1 (PON1) activity compared to reference values, 8-oxoG levels were unchanged compared with those of healthy control women, lipoperoxide ranks were
296 Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants
significantly increased compared with those of premenopausal women and an indirect cor- relation between PON1 arylesterase (PON1 A) activity and lipoperoxide levels, between PON1 A activity and atherogenic index, between age and TAS, and between age and 8-oxoG levels. Moreover perimenopausal women had higher total cholesterol levels and PON1 A levels were lower than physiological values (table 2) [44].
Variable TCH TG LDL HDL Atherogenic index (TCH/HDL) PON1 A Pon1 L Homocysteine Glycemia Uric acid
Average?SD or median 5.673?0.856 mmol/L 1.424?0.66 mmol/L 3.103?0.649 mmol/L 1.563?0.445 mmol/L 3.853?1.009
89.628?14.798 U/mL 12.213?2.956 U/mL 8.48?2.97 ?mol/L 5.43?0.65 mmol/L 246.5 (209.9-296.9) ?mol/L
Physiological values 5.17 mmol/L 1.9 mmol/L 3.5 mmol/L 1.4 mmol/L 5.2
100-200 U/mL 13-20 U/mL 12 ?mol/L 4.2-6.2 mmol/L 339?mol/L
Table 2. Data showing departures from normality are expressed as median values with the respective lower and upper quartile. The boldfaced entries indicate values beyond the reference range. PON1 A, paraoxonase with arylesterase activity; PON1 L, paroxonase-1 with lactonase activity.Paroxonase-1 levels in perimenonausal women [44].
Another finding is the lipoperoxide level which was significantly increased in perimeno- pausal women (Table 3). The levels of the marker of oxidative damage to DNA-8-oxoG were not statistically between pre and perimenopausal. In contrast women in perimenopause had repair ability 4 times higher compared with premenopausal women and significantly in- creased plasma total antioxidant capacity (TAS) [44] (Table 3).
Variable TAS Lipoperoxides 8-oxoG Repair ability
Perimenopausal women 1.532?0.095 mmol/La 37.995 (32.035-44.849) nMol/mLa 0.464 (0.283-0.957) per 106 G 36.919% (30.679%-47.046%)a
Controls (premenopausal) 1.230?0.100 mmol/mL 28.096 (23.103-30.850) nmol/mL 0.503 (0.337-0.674) per 106 G 10.539% (8.665%-11.475%)
Table 3. Data showing departures from normality are given as median values with the respective lower and upper quartile. athese values are significantly different (P0.005) compared with controls. Profile oxidant and antioxidant between premenopausal and perimenopausal women [44].
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